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| __NOTOC__
| | #REDIRECT [[Quinapril#Pharmacology]] |
| {{Quinapril}}
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| {{CMG}}; {{AE}} {{AM}}
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| ==Clinical Pharmacology==
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| ====Mechanism of Action====
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| Quinapril is deesterified to the principal metabolite, quinaprilat, which is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of [[angiotensin I]] to the vasoconstrictor, [[angiotensin II]]. The effect of quinapril in hypertension and in [[congestive heart failure]] (CHF) appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to [[angiotensin II]], [[norepinephrine]] or [[epinephrine]]. Angiotensin II also stimulates the secretion of [[aldosterone]] from the [[adrenal cortex]], thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L . Removal of angiotensin II negative feedback on renin secretion leads to increased plasma [[renin]] activity (PRA).
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| While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. ACCUPRIL was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in nonblacks. ACE is identical to kininase II, an enzyme that degrades [[bradykinin]], a potent peptide vasodilator; whether increased levels of [[bradykinin]] play a role in the therapeutic effect of quinapril remains to be elucidated.
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| ====Pharmacokinetics and Metabolism====
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| Following oral administration, peak plasma quinapril concentrations are observed within one hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25–30%) when ACCUPRIL tablets are administered during a high-fat meal. Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5–80 mg doses and 40–160 mg in multiple daily doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins.
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| In patients with renal insufficiency, the elimination half-life of quinaprilat increases as [[creatinine clearance]] decreases. There is a linear correlation between plasma quinaprilat clearance and [[creatinine clearance]]. In patients with end-stage renal disease, chronic [[hemodialysis]] or continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat may be reduced in elderly patients (≥65 years) and in those with heart failure; this reduction is attributable to decrease in renal function. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.
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| ====Pharmacodynamics====
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| Single doses of 20 mg of ACCUPRIL provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to [[angiotensin I]] is shorter-lived, with a 20 mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of [[angiotensin II]] levels at 24 hours by doses of 20–80 mg.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = ACCUPRIL (QUINAPRIL HYDROCHLORIDE) TABLET, FILM COATED [PARKE-DAVIS DIV OF PFIZER INC] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=63cf5651-d52c-4d27-9fd4-ed9cd9724dff | publisher = | date = | accessdate = }}</ref>
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| ==References==
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| {{Reflist}}
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| {{FDA}}
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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